An interdisciplinary team of clinical and experimental nutritionists, hepatologists, internists and morphologists plans to determine 1) whether patients who use drugs have altered hepatic vitamin A levels 2) whether drugs and food additives lower hepatic vitamin A in the rat and whether they induce abnormalities of vitamin A metabolism in the liver which might explain the changes 3) whether there is an associated deleterious effect on the liver 4) to what extent drugs and food additives enhance vitamin A requirements. Vitamin A levels will be measured in liver biopsies of patients exposed to various drugs. Possible relationship between lowering of hepatic vitamin A and alterations of the Golgi, microtubules and lysosomes will be assessed. The effects of drugs and food additives on hepatic vitamin A status will also be evaluated in experimental models to determine possible mechanisms whereby drug administration can lower hepatic vitamin A, including bile excretion and increased metabolism of retinoic acid in "induced" microsomes. The possibility of a selected interaction of retinoic acid with specific forms of cytochrome P-450 will be evaluated in isolated microsomes and in reconstituted microsomal systems. The role of lowered hepatic vitamine A in the pathogenesis of liver disorders will be assessed in rats rendered vitamin A deficient and potentiation by drug administration will be evaluated. Studies will focus on alterations of the Golgi apparatus with the evaluation of impairment of lipoprotein secretion including abnormal glycosylation. Microtubular alterations will be assessed by morphometry and immunofluorescence. In addition, tubulin will be measured by radioimmunoassay. Possible lysosomal alterations will be determined by electron microscopy, histochemistry and measurement of lysosomal enzymes in total homogenates (with and without lysosomal disruption by Triton), isolated lysosomes and in the blood. To obtain the information needed for optimal vitamin A therapy, potentiation by drugs or ethanol of the toxicity of vitamin A supplementation will be determined in the rat and in patients participating in a program of vitamin A treatment for sexual dysfunction. The aim of this study is not only to increase our understanding of the abnormalities of vitamin A metabolism associated with drug use (including the impact on the pathogenesis of liver dysfunction) but also to provide information needed for the prophylactic and therapeutic use of vitamin A.